Multicenter Genetic, Epigenetic & Expression Analysis of DCIS outcome predictors

描述（由申请人提供）：本项目的目标是确定从导管原位癌（DCIS）发展为浸润性乳腺癌过程中发生的分子变化。这是至关重要的，因为只有在达到组织浸润的里程碑之后，癌症才有可能转移并杀死患者。浸润性乳腺癌具有多种分子改变，这些改变在从ADH到导管原位癌（DCIS）再到浸润性乳腺癌的进展过程中顺序获得。我们将确定可能是DCIS特有的或可能随着恶性潜能的增加而累积的遗传改变。7基本原理：虽然导管原位癌（DCIS）的治愈率超过90%，但这是以相当大的治疗相关发病率为代价的。我们迫切需要的预后标志物，将确定关键的遗传变异预测DCIS的长期结果，因为大多数DCIS从来没有成为浸润性癌，大概是因为他们缺乏关键的遗传变化，复制寿命，或只是必要的时间这样做。我们的实验设计利用了最近的技术发展，这些技术发展允许对DNA样品进行全基因组检测以检测遗传和表观遗传改变，即使是在从档案DCIS样品中获得的非常有限的材料中。DCIS可能代表一个阶段，在该阶段尝试克隆进化的各种途径，直到遗传和/或表观遗传变化的特定组合允许组织侵入。有迹象表明，基因突变和表观遗传沉默都可能在致癌作用中起作用，并且这些替代品可以互换使用，甚至在同一癌细胞中以互补的方式使用。因此，有必要对这两种类型的变化进行综合分析。7设计：多中心、纵向、病例对照研究。我们已经确定了具有已知结果的纯DCIS病例的独特队列，以使100例病例和100例对照的多中心全基因组筛选研究成为可能，该研究最初将限于白人起源的患者，以获得同质的患者人群，并最大限度地成功验证我们的假设，即DCIS中存在预后标志物。将通过定量PCR方法进一步表征感兴趣的候选标志物，目的是创建单一的、预后性的多重PCR特征，其可用于通常在DCIS评价的诊断阶段获得的有限临床材料。然后，我们将在100例进行性疾病的DCIS病例与100例保持无疾病的DCIS病例的独立测试队列中验证该检测方法，该队列从爱荷华州SEER残留组织库（RTR）提供的基于人群的库中获得。我们还将使用位于夏威夷的一个额外的基于人群的储存库，以测试从高加索人样本开发的预后特征是否可以成功地用于不同的种族群体。这将指导未来的工作，特别是关于探索在不同人群中的多重检测的预测能力的必要性。

DESCRIPTION (provided by applicant): The goal of this project is to identify the molecular alterations that occur in the progression from ductal carcinoma in situ (DCIS) to invasive breast cancer. This is of critical importance because it is only after the milestone of tissue invasion has been achieved that a cancer has the potential to metastasize and kill a patient. Invasive breast cancers harbor multiple molecular alterations that were sequentially acquired during progression from ADH to ductal carcinoma in situ (DCIS) to invasive breast cancer. We will identify the genetic alterations that may be specific to DCIS or may be cumulative with increasing malignant potential. 7Rationale: While the cure rate for ductal carcinoma in situ (DCIS) is over 90%, this comes at the cost of considerable treatment-related morbidity. We urgently need the prognostic markers that would identify key genetic alterations predictive of the long-term outcome of DCIS, since most DCIS never become invasive carcinomas, presumably because they lack critical genetic changes, the replicative lifespan, or simply the time necessary to do so. Our experimental design exploits recent technological developments that permit genome- wide testing of DNA samples for genetic and epigenetic alterations, even in the very limited material available from archival DCIS samples. DCIS may represent a stage at which various pathways of clonal evolution are attempted, until a particular combination of genetic and/or epigenetic changes allows tissue invasion. Indications are that genetic mutations and epigenetic silencing may both be operative in carcinogenesis, and that these alternatives may be used interchangeably, even in a complementary fashion in the same cancer cell. Therefore, a combined analysis of both types of alterations is necessary. 7Design: This study is designed as multicenter, longitudinal, case-control study of DCIS. We have identified unique cohorts of pure DCIS cases with known outcomes to enable a multicenter genome-wide screening study of 100 cases and 100 controls, which will be initially limited to patients of Caucasian origin in order to obtain a homogenous patient population and maximize the probability of successfully validating our hypothesis that prognostic markers exist in DCIS. Candidate markers of interest will be further characterized by quantitative PCR methods, with the goal of creating a single, prognostic multiplex PCR signature that can be used on the limited clinical material typically obtained in the diagnostic phase of the evaluation of DCIS. We will then validate the assay in an independent test cohort of 100 cases of DCIS with progressive disease vs. 100 cases of DCIS that remain disease free, obtained from the population-based repository provided by the Iowa SEER residual tissue repository (RTR). We will also use an additional population-based repository located in Hawaii, to test if the prognostic signature developed from Caucasian samples can be used successfully in a different ethnic group. This will guide future work, particularly regarding the necessity of exploring the predictive power of the multiplex assay in different populations.